Systemic T cell immunity is intact in both cancer patients and in murine models but Tumor Infiltrating Lymphocytes (TIL) are defective in cytolytic function. Available data describing TIL dysfunction suggests that tumor-induced suppression of TIL effector phase function is a common characteristic of cancer which may contribute to tumor escape from antitumor immune response. The Frey lab has determined that TCR-mediated signaling is defective in both nonlytic CD8+ TIL in situ and when freshly-isolated and assayed in vitro: upon conjugation with cognate tumor cells in vitro TIL do not activate tyrosine kinases or flux calcium. Since signaling is required for T cell effector phase function, defective TIL signal transduction is undoubtedly the basis for the nonlytic phenotype. The signaling and lytic defects are transient: when TIL are purified and briefly cultured in vitro signaling is restored coincident with recovery of lytic function. The signaling defect is proximal in the TCR-mediated signaling cascade: contact with tumor cells in vitro causes rapid dephosphorylation of the activation motif in p56lck (Y394) therein preventing propagation of the activating signal. In nonlytic TIL, but not in lytic TIL, the inhibitory phosphatase Shp-1 is activated and co-localizes with p56lck at the TIL:target cell contact site. TIL signaling and lytic defects are completely restored upon purification and brief culture in vitro including dissociation of Shp-1 from the TCR complex and reduction of Shp-1 phosphatase activity. Recovery of defective TIL signaling in vitro is blocked by co-culture with tumor cells implying a contact-dependent, fast-acting 'switch'. Also, if TIL are first 'recovered'prior to co-culture with tumor cells (by brief culture in the absence of tumor cells), the TIL proximal TCR signaling defect is re-introduced. Upon culture of TIL with non-cognate tumor cells or tumor associated myeloid derived suppressor cells, TIL signaling and lytic functions are not affected. These observations show that tumor cells deliver an inhibitory signal to TIL resulting in recruitment of activated Shp-1 to the TCR complex which in turn inactivates proximal TCR-mediated signal transduction and therein effector phase function. Identification of the mechanism by which Shp-1 is recruited to the TIL TCR is a major objective of the proposed project. My long-term goal is to define the mechanism by which tumors escape elimination by the immune response which will have implications for the rational design of effective immunotherapeutic tools for treatment of cancer, as well as contribute to our understanding of how antitumor T cell response is regulated during tumor growth.